Apoptosis is a form of programmed cell death, by which an organism eliminates extraneous or harmful cells. Apoptosis plays a role in normal development and homeostasis, as well as in diseases such as cancer and neurodegenerative diseases.
Apoptosis occurs via the activation of intrinsic cell-suicide programs; activation is regulated by many different signals, both intracellular and extracellular. Various viral and metazoan apoptosis inducer genes have been identified; inhibitors of apoptosis (IAP) proteins have also been identified that act to suppress apoptosis.
At least three apoptotic activator proteins have been identified in Drosophila melanogaster: reaper (rpr), head involution defective (hid) and grim. The N-terminal sequences of these proteins are highly conserved. Avdonin et al., Proc. Natl. Acad. Sci. USA 95:11703 (1998). Proteins that inhibit apoptosis (IAPs) have also been identified in Drosophila. Hay et al., Cell 83:1253 (1995); Wing et al., Cell Death Differ. 5:930 (1998).
The product of the reaper gene is required for programmed cell death in Drosophila. Cell death induced by the reaper protein has been shown to be blocked by the baculovirus p35 protein, a viral product that inactivates proteases. White et al., Science 271:805 (1996).
The Drosophila Grim protein is also an activator of apoptosis, independent of Reaper. Expression of Grim RNA coincides with the onset of programmed cell death during embryonic development, and ectopic induction of grim has been show to trigger extensive apoptosis in transgenic animals and in cell culture. Similar to the Reaper protein, cell killing by grim can be blocked by coexpression of the viral p35 product. The grim gene product has been postulated to function in a parallel cell death signalling regime that activates a common set of downstream apoptotic effectors. Chen et al., Genes Dev. 10:1773-1782 (1996).
Viral infection of host cells, and replication therein, is often associated with inhibition of apoptosis to enable viral replication and the subsequent stimulation apoptosis of the host cells for viral particle release. Certain viral gene products have been shown to specifically inhibit or induce apoptosis. However, many viruses additionally encode proteins that inhibit apoptosis, prolonging the survival of infected cells and thereby aiding viral replication or viral persistence in the host.